Weight control via dietary calorie restriction (DCR) or physical activity has a profound inhibitory effect on carcinogenesis in animal models. However, the underlying mechanisms are not fully defined. Our previous studies conducted in a DMBA-initiated and TPA-promoted mouse skin cancer models demonstrated weight loss by 20% of DCR-fed animals or moderate treadmill exercise without compensatory increase in food intake inhibited skin tumorigenesis by suppressing TPA-induced PKC-Raf- MAPK-AP-1 signal pathway. We and others have also found that the plasma levels of IGF-1 and leptin are significantly reduced in DCR- or exercise-induced weight controlled mice. The reduction of circulating IGF-1 levels corresponded to a concomitant inhibition of IGF-1-dependent signaling cascades, i.e., Ras-MAPK- proliferation and PI3K-Akt-antiapoptosis, suggesting a crosstalk mechanism in diminishing TPA-promoted signaling in the epidermis of mice. However, restoration of IGF-1 to the control levels in DCR-fed mice did not reverse DCR-induced anti-tumorigenesis. These observations, coupled with our preliminary data that the inhibition of skin tumorigenesis by DCR was abrogated by implanting both IGF-1 and leptin, constitute the first in vivo evidence for a novel hypothesis that adipocyte-secreted leptin might act as a co-promoter for mitogenic effect of IGF-1 on tumorigenesis. The rationale for this project is that understanding weight loss- induced cancer prevention via hormone-mediated mechanisms can help to clarify new cancer etiologic factors of obesity that exists in epidemic proportions in the USA. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine whether the restoration of IGF-1 and leptin reverses the inhibition of tumorigenesis by exercise-induced leanness via the same mechanisms as DCR;2) Assess whether selectively decreasing leptin but not IGF-1 levels by lipectomy in high fat diet-induced obese mice has inhibitory effects on mitogenic signaling cascades. Under these aims, multiple manipulations of energy balance (exercise with or without controlled diet intake and overfeeding by high fat diet), hormone level modification (negative or positive energy balance-induced hormone changes, osmotic minipump restoration, and lipectomy), and overall bioinformatics changes via lipidomics, microarray, and proteomics with emphasis in hormone- and TPA-induced cascades have been established as feasible in the applicants'hands. The approach is innovative, since it utilizes unique methods based on existing animal models to discover the complexity of hormonal etiology in body weight-related cancer risk. The proposed research is significant because it is expected to advance our insight into how exercise-modified body weight is related to cancer. Ultimately, such knowledge has the potential to lead to the promotion of new prevention and treatment strategies. PUBLIC HEALTH RELEVANCE: Overweight or obese due to excessive calorie intake and sedentary lifestyle has been closely associated with increased cancer risk. However, the underlying mechanism is not clear. This research will provide novel evidence why weight control via physical activity may protect against cancer.